1, 4, 17(20)-pregnatrienes



United States atent 1,4,11(20)-PREGNATR[ENES Jerome Korman, Portage Township, Kalamazoo County, and John A. Hogg, Kalamazoo Township, Kalamazoo County, Mich, assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Original application January 31, 1955, Serial No. 435,316. Divided and this application Decemher 6, 1955, Serial No. 551,231

6 Claims. (CL ass-239.5

This invention relates to intermediates in the preparation of A -hydrocortisone and Zl-esters of A -hydrocortisone. This application is a division of application S. N. 485,316, filed January 31, 1955, and a continuation-inpart of application S. N. 406,364, filed January 26, 1954, now Patent No. 2,774,775.

It is an objectof the present invention'to provide intermediates for novel n -hydrocortisone and 2l-esters thereof. Another object is the provision of a process for the production of said intermediates. Other objects will be apparent to those skilled in the art to which this invention pertains. Y

The novel n -hydrocortisone and preferred 21-esters thereof are represented by the following formula:

wherein R is hydrogen or the acyl radical of an organic carboxylic acid, preferably containing from one to twelve carbon atoms, and especially hydrocarbon carboxylic acids containing from one to eight carbon atoms, particularly acetic acid. n -hydrocortisone (I, R is H) and n -hydrocortisone acetate (1, R is acetyl) are the preferred compounds.

The novel intermediates of the present invention have the following structural formula: 1

and include the ill-organic carboxylic acid esters thereof wherein the acyl radical contains from one to twelve carbon atoms, inclusive. It also includes the 3-pyrrolidyl enamines thereof and the 3-cyclic ketals thereof in which the ketal forming glycol is a l oweiwaliphatic alkylene glycol such as ethylene glycol. The invention moreover includes the 3-en ol ethers of the above compound.

arthritics.

2 n -hydrocortisone and ZI-esters thereof possess modified adrenal cortical hormone activity, the 21-esters modifyiug the activity of n -hydrocortisone somewhat, e. g, prolongation of activity, enhanced activity by some routes of administration, greater oil and/or Water solubility, improved taste, greater stability, lower-melting, etc. These compounds possess marked anti-inflammatory activity and are valuable in the treatment of rheumatoid In addition, these compounds possess other activities not ordinarily associated with hydrocortisone and esters thereof, e. g, androgenic activity.

n -hydrocortisone and 21-esters thereof, especially 21- esters wherein the acyl radical is that of an organic carboxylic acid containing from one to twelve carbon atoms, inclusive, preferably hydrocarbon carboxylic acids containing from one to eight carbon atoms, inclusive, e. g., lower-aliphatic, especially N-hydrocortisone acetate, having an order of activity surprisingly greater than hydrocortisone and its 2l-esters, in some instances being up to ten times greater as an anti'arthritic without possessing significant salt retention activity. Furthermore, their spectrum of activity is surprisingly different from the corresponding hydrocortisone and esters thereof, as well as dillering in degree in the, activities common to both the natural hormone and the A compound. Furthermore, they are frequently useful in the treatment of rheumatoid arthritics and other arthritics who have not responded to therapy with hydrocortisone acetate or hydrocortisone.

n -hydrocortisoue, and 21-esters thereof, e. g., the 21-- formate, acetate, propionate, butyrate, cyclopentylpropionate, dimethylacetate, trimethylacetate, phenylacetate,

phenylpropionate, succinate, benzoate, and. the like, are

prepared in the same manner disclosed, in application Serial No. 346,274 filed April 1, 1953, now Patent No.

2,790,814, for the production of hydrocortisone, i. e..

protecting the 3-keto group of methyl 3,11-diketo-l,4,l7 (20)pregnatriene-21-oate with an eno lether, cyclic ketal,

or preferably with a pyrrolidyl enamine, then reducing the 2 1-carbonyloxy group with lithium aluminum hydride,. lithium borohydride, or the like, followed by the hy-' ,drolysis, usually with acid, of the enamine group to regenerate the n -ffi-keto group, acylation of the 21- hydroxy group to produce an llfl-hydroxy-2laacyloxy- 1, 1,17,60)pregnatrieneG-one, and then introducing the 17a-hydroxy20-keto group by reaction of the thusproduced 21-acyloxy steroid with hydrogen peroxide and a. small proportion of osmium tetroxide, to produce an 115,

These reactions may be illustrated as follows:

CH3 CH2 wherein R represents a suitably protected 3-keto group, i. e., an enamine, cyclic ketal or enol ether group; and Ac is the acyl radical of an acid as described above; and the dotted line represents a 4(5)-double bond which is present when the protecting group is an enamine' or enol ether.

The novel N-hydrocortisone compounds are useful also.

in the preparation of other synthetic steroids possessing adrenal cortical hormone activity of a surprising order and quality. For example, treatment of n -hydrocortisone acetate with a dehydrating agent, e. g., p-toluenesulfonic acid, P001, in pyridine, HCl in acetic acid, acetic or formic acid in the presence of BF is productive of A -hydrocortisone acetate, a compound which possesses adrenal cortical hormone activity also. Reaction of this latter compound with N-bromoacetamide in the presence of aqueous perchloric acid is productive of 9abromo-l1,8,l7a-dihydroxy-2l-acetoxy-l,4 pregnadiene 3,20-dione which, when reacted with sodium methoxide in methanol, is converted to 9:ll-fl-oxido-lh-hydroxy- 21-acetoxy-1,4-pregnadiene-3,20-dione. pound in methylene chloride at minus fifteen degrees centigrade with hydrogen fluoride is productive of 9oc-fl1l0l'0- 11B,17a-dihydroxy-21-acetoxy-1,4-pregnadiene-3,20 di one, a compound with marked adrenal cortical hormone activity. The corresponding 9a-chloro compound which has similar activity, is prepared by substituting hydrogen chloride for the hydrogen fluoride in the last step.

The novel A -compounds, especially n -hydrocortisone and n -hydrocortisone acetate, are useful in the treatment of maladies in both humans and valuable domestic animals, e. g., inflammations of the skin, nose, ears, and eyes caused by bacterial or fungal infections, contact dermatitis or physiological maladjustment.

The novel 11B,17a,21-trihydroxy-l,4-pregnadiene-3,20- dione and 1lfi,l7a-dihydroxy-2l-acyloxy-1,4-pregnadiene- 3,20-diones are especially useful as pharmaceutical compositions and mixtures, e. g., ointments, lotions, greases, creams, aqueous suspensions, etc., for topical use. Examples of especially advantageous pharmaceutical compositons are listed below. Although the examples are to the 11/3,17a,2l trihydroxy 1,4 pregnadiene-3,20-dione and 11,8,17a-dihydroxy-2l-acetoxy-1,4-pregnadiene-3,20 dione, it is to be understood that the other 21-esters are substitutable therein.

The novel 11B,l7u-dihydroxy-2l-acetoxy-1,4 pregna diene-3,20-dione is advantageously employed as a topical ointment for use on the skin or in the eyes in the treat- Mixing this com Lbs.

30 percent wool fat, USP 100 percent white mineral oil, USP 125 p 0.6 percent neomycin sulfate (microatomized) 3 ment of topical inflammatory conditions. A suitable topical and ophthalmic ointment has the following composition:

White petrolatum, USP, q. s., ad. 500 lbs.

The wool fat and petrolatum are melted and strained into a suitable container. The temperature is adjusted to 113 degrees Fahrenheit. The steroid is mixed with ninety pounds of strained mineral oil and milled through a Fitzpatrick mill. The mill is washed with 35 pounds of strained mineral oil. The steroid mixture and mill washings are added to the base and the base then stirred with a high speed mixer until congealed.

Incorporation of an antibiotic in the oitment, e. g., oxytetracyclin, chlortetracyclin, tetracyclin, penicillin, and especially neomycin sulfate or a sulfonatnide, e. g., 3,4 dimethyl 5 sulfanilamido-isoxazole, has surprising therapeutic advantages each active ingredient potentiating and supplementing the useful properties of the other in a fashion more particularly described in the copending application of Dale, S. N. 458,679, filed September 27, 1954. Such an ointment, exemplified by the use of neomycin sulfate,.is as follows:

1.0 percent 11B,17et-dihydroxy-2l-acetoxy-lA-pregnadiene-3,20-dione (micronized) 5 White petrolatum, USP, q. s., ad. 500 lbs.

An injectable composition suited for suspending the compounds which has advantages in the treatment of Addisonian crisis and in shock is as follows:

Water for injection, sufficient to make up 1.0 cc.

The suspending agents in this vehicle, i. e., the combination of polyvinylpyrrolidonesodium carboxymethylcelluose, or a polyalkylene glycol, are particularly useful when used in conjunction with the novel A -physiologically active steroids afford an especially useful combination which produces stable suspensions or suspensions which are readily resuspendible which prevents undue caking as more particularly pointed out in the copending application of Cronin and Hennig, S. N. 427,676, ,filed May 4, 1954, and of Sponnoble and Hamlin, S. N. 471,512, filed November 26, 1954.

Another composition suitable for injection has the following composition:

2.5 grams sterile micronized 11B,17u,21-trihydroxy-l,4-

pregnadiene-3,20-dione 3.0 grams polyethylene glycol 4000 0.9 gram sodium chloride gran, USP

0.4 gram Tween 1.5 grams benzyl alcohol, N. P. Q. s., cc. water for injection The polyethylene glycol, sodium chloride, Tween 80 and benzyl alcohol are dissolved in water and the solution sterilized by filtration. Sterile l.1f3,170t,21-tl'lhyd1OXy-1,4-

foic acid methyl ester.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 .i-ethylene glycol ketal of 3,11-diketo-1,4,17(20)- pregnatriene-Zl -ic acid methyl ester To a solution of 1. grams (0.0042 mole) of 3,1l-dilreto-1,4,17 ()-pregnatriene-21-acid methyl ester dis solved in 150 milliliters of benzene was added 7.5 milliliters of ethylene glycol and 0.150 gram of para-toluenesulfonic acid and the whole was then heated with .stirring at the reflux temperature of the, reaction mixture for 5.5 hours. The cooled reaction mixture was washed EXAMPLE 2 3 ethylene glycol ketal of 11fl,21 dihydr0xy-1,4,17(20 pregnatriene-3-0ne A solution of 1.50 grams of the Cl-ethylene glycol ketal of 3,11diketo-1,4,17(20)-pregnatriene21 oic acid methyl esterin seventy milliliters of benzene was added drop- .wise to a stirred mixture of 1.50 grams of lithium aluminurn hydride and fifty milliliters of anhydrous ether. When addition was complete, the reaction mixture was refluxed forone-half hour whereafter the mixture was cooled to room temperature. Fifty milliliters of water was then cautiously added to the stirred reaction mixture to decompose the excess-lithium aluminum hydride, followed by 200 milliliters of methylene chloride. The whole was then centrifuged to facilitate separation of the organic and aqueous phases. The organic phase was separated, the solvent distilled and the residue was crystallizedfrom a mixture of ethyl acetate and Skellysolve B hexane hydrocarbons to give crystalline 3-ethylene glycol ketal of 115,21-dihydroxy-1,4,17(20)-pregnatriene-3-one.

EXAMPLE 3 11 13,21 -dihydr0xy-l ,4 ,1 7 (20 -pregnatriene-3.-0ne

A solution of 0.572 gram (0.0015 mole) of the 3-ethy1- ene glycol ketal of 11,8,21-dihydroxy-l,4,l7.(20)-pregnatriene-3-one in forty milliliters of acetone was diluted with water to a volume of fifty milliliters and eight drops of concentrated sulfuric acid was then added thereto, whereafter the reaction mixture was kept at room temperature for 24 hours. The reaction mixture was then made alkaline by the addition of a saturated aqueous sodium bicarbonate solution and the acetone was then evaporated from the mixture. Methylene chloride and more water were then added, the methylene chloride layer removed, and the solvent distilled therefrom. The residue, after drying in vacuo, consisted of 11;3,21-dihydroXy-1,4,17 (20)-pregnatriene-3-one.

EXAMr E 4 1 1,9,21-dilzydr0xy-1 ,4,] 7(20) -pregnatriene-3-one A solution of 1.0 gram of 3,1l-diketo-l,4,17(20);pregnatriene-Zl-oic acid methyl ester, 0.5 milliliter of pyrrolidine, and 1.5 milligrams of para-toluenesulfonic acid in 100 milliliters of benzene were heated at the reflux temperature of the mixture for 45 minutes, withjthe concomitant removal of the water of reaction. 'Thesolveht was distilled from the mixture to leave a residue consisting essentially of 3 pyrrolidyl 11-keto-1,3,5,17(20)- pregnatetraene-Zl-oic acid methyl ester.

This residue was dissolved in five milliliters of benzene, a suspension of 376 milligrams of lithium aluminum 'hy- .dridein 290 milliliters of etherwas added thereto overa periodof five minutes, and the mixture was stirred at room temperature for. one hour. Three milliliters of ethyl acetate was added to destroy excess lithium aluminum hydride, followed by five milliliters of water. The ether was distilled at atmospheric pressure from the mix- .ture to. leave a residue consisting essentially of 3-pyrrolidyl- 115,21-dihydroxy-1,3,5,17 (20)-pregnatetraene and inorganic material.

This crude distillation residue was mixed with 327 milliliters of methanol at 55degrees centigradeuntil solution was eifected and then cooled to 37 degrees centigrade. 116.5 milliliters of an aqueous five percent sodium hydroxide solution was added thereto and heating of the mixture at about forty degrees centigrade was continued for ten minutes. The solution was neutralized with 3.5 milliliters of acetic acid at below 37 degrees centigrade and the solvent distilled therefrom at reduced pressure and at a temperature below 45 degrees centigrade. The milliliters of residue was mixed with a mixture of 370 milliliters of water and 170 milliliters of concentrated sulfuric acid, stirred for twenty minutes and then filtered and Washed with water to give 1l;8,21-dihydroxy-l,4,- 17(20)-pregnatriene-3-one which melts at 149 to 153 degrees centigrade when recrystallized from ethylene dichloride, has an' [M of plus 117 degrees in chloroform, and an 6 of 14,700. The melting point varies considerably, depending upon the crystallizing solvent.

EXAMPLE 5 1 1 ,B-hydroxy-Z] -acet0xy-1 ,4,] 7 (20 -pregnatriene-3-01ze Asolution. of 0.518 gram of 11,8,21 -dihydroxy-1,4,- 17 (20)-pregnatriene-3-one in five milliters of pyridine was mixed with two milliliters of acetic anhydride and the whole was then maintained at room temperature for seventeen hours whereafter crushed ice was added thereto. The precipitated 11 fl-hydroxy-Z l-acetoXy 1,4, l7 (20)-pregnatriene-3-one was filtered therefrom, dissolved in benzene and then chromatographed over a column of 75 grams of Florisil synthetic magnesium silicate. The column was developed with v75-rnilliliter portions of Skellysolve B hexane hydrocarbons containing increasing proportions of acetone. There was thus eluted llfi-hydroxy-Zl-acetoxy- 1,4,17(20)-pregnatriene-3-one from the column.

Similarly, 11,8,21-dihydroxy-1,4,17(20l-pregnatriene-3- one is converted to other 11,8-hydroxy-21-acyloXy-1,4, 17(20)-pregnatriene-3-ones by esterification of the 21- hydroxy group, e. g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst,

etc., 115,21 dihydroxy-1,4,17(20)-pregnatriene-3-one is' similarly converted to other 21-esters thereof. Examples of 1 lfi-hydroxy-Z1-acyloxy-1,4, 17 (20 )-pregnatrien3-oi1e prepared include those wherein the acyl group is the acyl radical of, for example, a lower-aliphatic acid, e. g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, the optically active abietic, a-ethylisovaleric, an acyclic acid, e. g., 3fl-hydroxycholanic, 3 8-hydroxyetiocholanic, cyclopropylideneacetic, a cycloaliphatic acid, e. g., cy'clopentylformic, cyclopentylacetic, fi-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, p-cyclohexylpropionic, an aryl or alkaryl acid, e. g., benzoic, 2,3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic,

2,4,6-trimethylbenzoic, 2,4,6-triethylbenzoic e-naphthoic,

3-methyl-e-naphthoic, an arallryl acid, e. g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (which can be converted to Water soluble, e. g., sodium salts) .e. g., succinic, glutaric, .a methylglutaric, p-methylglutaric, ;8,fi-dimethylgultaric, adipic, pimelic, suberic, a hydroxyacid, e. g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannonic, gluconic, salicylic, an ammoacid, e. g., glycine, diglycollarnic, .triglycollamic, methylglycine, dimethylglycine, diethylglycine, paraaminosalicylic, para-aminobenzoic, other hetero-substituted acids, e. g., ethylmercaptoacetic, benzylrnercaptoacetic, cyanoacetic, chloroacetic, fiuoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, 2,3,4-trirnethoxybenzoic, u napthoxyacetic, fi pyrrolidylpropionic, carbamic acids, e. g.,carbamic acid, phenylcarbamic, n-butylcarbarnie, dimethylcarbarnic, diethylcarbarnic, allophanic, or a heterocyclic acid, e. g., ,B-furylcarboxylic, N-methylpyrrolidyl-2-carboxylic, a-picolinic, indole-2-carboxylic, 6-hydroxyindolyl-3 acetic, N-methylmorpholyl-2-carboxy1ic, lysergic, pyrrolyl-Z-carboxylic, or other aryl acid.

EXAMPLE 6 1 1fl-hydr0xy-2I -acelxy-1 ,4,1 7 (20) -pregnadiene-3-0ne A solution of 6.6 grams of 11,8,21-dihydroxy-L4, 17(20)-pregnatriene-3-one in fifteen milliliters of pyridine, prepared at room temperature, was mixed, at zero degrees centigrade, with fifteen milliliters of acetic anhydride. After one hour at room temperature, copious crystallization had taken place in the resulting mixture. After stirring for a total of eighteen hours, the mixture filtered and the cake washed with a 50:50 mixture of pyridine and acetic anhydride, followed by water. The cake was dried to give 4.92 grams of llfi-hyclroxy-Zlacetoxy-1,4,17(20)-pregnatriene-3-one melting at 219 to 223 degrees centigrade. Mixing the original filtrate with Water gave 2.12 grams of less pure llfi-hydroxy-Zlacetoxy-1,4,17(20)-pregnatriene-3-one melting at 186 to 207 degrees centigrade.

EXAMPLE 7 1 15,1 7u,21 -lrihydr0xy-J ,4 -pregnatliene-3,20-dione .d -hydrocortisone) To a stirred suspension of 0.124 gram (0.00033 mole) of 11 ,B-hydroxy-Zl-acetoxy 1,4,17(20) pregnatriene 3- one in two milliliters of tertiary butyl alcohol was added 0.26 milliliter of a 2.6 molar solution of hydrogen peroxide in tertiary butyl alcohol and 0.30 milliliter of a solution of 1.00 gram of osmium tetroxide in 100 milliliters of tertiary butyl alcohol. An additional 0.50 milliliter of the above-described osmium tetroxide solution was added to the reaction mixture during the next thirty hours. After the first four hours of reaction time the reaction mixture darkened and became homogeneous. The reaction mixture was stirred and maintained at room temperature for anadditional 84 hours, whereafter water and methylene chloride were added thereto. The whole was distilled at reduced pressure to remove the organic solvents and the product was extracted from the residue with methylene chloride, whereafter the extract was freed of solvent by evaporation. The residue, after dissolving in a mixture of five milliliters of methanol and one milliliter of a solution of 0.30 gram of sodium sulfite in five milliliters of water, was heated on a steam bath for thirty minutes. The 1lfl,17a,21-trihydroxy-l,4-pregnadiene-3,20-dione was separated therefrom by extraction with methylene chloride, which was thereafter removed by distillation in vacuo. The residue consisted of l1B,l7a,21-trihydr0xy-l,4-pregnadiene-3,ZO-dione (A -hydrocortisone) and 11,67,170; dihydroxy 21 acetoxy-1,4- pregnadiene-3,20-dione as well as 11B,17ot,20,21-tetrahydroxy-1,4-pregnadiene 3-one. l l/3, 17 x,21 trihydroxy- 1,4-pregnadiene-3,ZO-dione melts at 232-2365 degrees centigrade and has an [111 of plus 100 degrees in dioxane. The yield of 1l,8,l7a,2l-trii1ydroxy-l,4-pregnadiene-3, ZO-dione is improved by the addition of from about two to seven molar equivalents, calculated on the starting steroid, of pyridine to the starting reaction mixture.

Esterification of the Zl-hydroxy group of llt-l,17a,21- trihydroxy-l,4-pregnadiene-3,20-dione, e. g., by reaction with the appropriate acid anhydride, acid chloride or bromide, ester by ester exchange, acid in the presence of an esterification catalyst, etc.,' is productive of 11,5317- dihydroxy-Zhacyloxy 1,4 pregnadiene-BQO dione, ere

amples of which include those wherein the acyl group is the acyl radical of, for example, a lower aliphatic acid, e. g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, heptanoic, octanoic, the optically active abietic, a-ethylisovaleric, an acylic acid, e. g., 3fi-hydroxycholanic, SB-hydroxyetiocholanic, cyclopropylideneacetic, a cycloaliphatic acid, e. g., cyclopentylformic, cyclopentylacetic, fi-cyclopentylpropionic cyclohexylformic, cyclohexylacetic, ,B-cyclohexylpropicnic, an aryl or alkaryl acid, e. g., benzoic, 2,3, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, 2,4, 6-triethylbenzoic, a-naphthoic, 3-methyl-u-naphthoic, an aralkyl acid, e. g., phenylacetic, phenylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (which can be converted to water soluble, e. g., sodium, salts), e. g., succinic, glutaric, ct-methylglutaric, ,G-methylglutaric, 19, 8- dimethylglutaric, adipic, pimelic, suberic, a hydroxyacid, e. g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannonic, gluconic, salicylic, an aminoacid, e. g., glycine, diglycollamic, triglycollamic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic, para-aminobenzoic, other hetero-substituted acids, e. g., ethylmercaptoacetic, benzylmercaptoacetic, cyanoacetic, chloroacetic, fluoroacetic, trichloroacetic, trifiuoroacetic, thioglycolic, 2,3,4-trimethoxybenzoic, ot-naphthoxyacetic, B pyrrolidyl propionic, carbamic acids, e. g., carbamic acid, phenylcarbamic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic, allophanic, or a heterocyclic acid, e. g., fi-furylcarboxylic, N-methylpyrrolidyl 2 carboxylic, w picolinic, indole-Z-carboxylic, 6-hydroxyindolyl-3-acetic, N-methylmorpholyl-Z-carboxylic, lysergic, pyrrolyl-2-carboxylic, or other acyl acid.

EXAMPLE 8 I 1 [3,1 7a-dihydroxy-21 -acetoxy-J,4-pregnadiene-3,ZO-dione Example 7. 7

EXAMPLE 9 1 1B,] 7a-dihydroxy-21-acetoxy-I,4-pregnadiene-3,20-

. dione To a solution of 1.11 grams (3 millimoles) of 11/3- hydroxy-Z1-acetoxy-1,4,17(20)-pregnatriene-3-one in fifty milliliters of tertiary butyl alcohol was added 1.5 milliliters Of pyridine followed by 5.02 milliliters of a tertiary butyl alcohol solution of 7.5 millimoles of N-methylmorpholine oxide peroxide (prepared by the reaction of 7.5

millirnoles of N-methylmorpholine with 15.0 millimoles of anhydrous hydrogen peroxide) in the tertiary butyl alcohol followed by 18.4 milligrams of osmium tetroxide in ten milliliters of tertiary butyl alcohol. The solution, which within five minutes had turned orange-red, was maintained for ninety minutes at 25 degrees Centigrade. At the end of this time, the now straw colored solution was mixed with 23 milliliters of 0.5 percent aqueous sodium sulfite at room temperature for 25 minutes and then concentrated, at reduced pressure, to a volume of about forty milliliters. This concentrate was stirred for thirty minutes and 35 milliliters of water was then added portionwise over a period of fifteen minutes. After stirring for 45 minutes, the solution which had gradually precipitated crystals, was filtered, washed with a 1:3 mixture of tertiary butyl alcohol and Water, and dried to give 670 milligrams of 11B,17m-dihydroxy-21-acetoxy-l,4-pregnadiene-3,20-dione which melted at 239 to 245 degrees centigrade. Recrystallization of these crystals from hot acetone raised the melting point to 240 to 242 degrees centigrade. The filtrate yielded crystals of 1113,17m-dihydroxy-Zl-acetoxy-l,4-pregnadiene-3,ZO-dione which, after two crystallizations from hot acetone, melted at 243 to 247 degrees centigrade, had an [ch of plus 114 degrees in dioxane and had an of 15,180.

Hydrogenating 11,8,17ot-dihydroxy-21-acetoxy-1,4-pregnadiene-3,20-dione with palladium on zinc carbonate catalyst in methanol is productive of 11B,17a-dihydroXy-21- acetoxypregnane-3,20-dine which, when brominated with bromine in glacial acetic acid and pyridine is productive of 4-bromo-l1B,17a-dihydroxy-21-acetoxypregnane-3,20- dione. Dehydrohalogenation of this compound with pyridine, collidine or semicarbazide followed by decomposition of the semicarbazone in the usual manner, is productive of 1Ifi,17u-dihydroxy-21-acetoxy-4-pregnene-3,20- dione.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of (1) 115,21-dihydroxy-1,4,17(20)-pregnatriene-3-one rep resented by the following formula:

CHaOH 10 (2) 21-organic carboxylic acid esters thereof wherein the acyl radical contains from one to twelve carbon atoms, inclusive, (3) the 3-pyrrolidyl enamine thereof, and (4) 3-cyclic ketals thereof of lower aliphatic alkylene glycols.

2. 1lfl-hydroxy-Zl-aeyloxyd,4,17(20) prcgnatriene-3- one represented by the following formula:

wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

3 1 1 B-hydroxy-Z 1-acetoXy-1,4, 17 (2O -pregnatriene/3- one.

4. 11B,21dihydroXy-1,4,17(20)-pregnatriene-3-one.

5. 3-pyrro1idyl-1118,2l-dihydroxy-l,3,5,17(2O)-pregnatetraene.

6. 3-alkylene glycol ketal of l1fl,21-dihydroXy-1,4,17- (20)-pregnatriene-3-one.

References Cited in the file of this patent UNITED STATES PATENTS 2,707,184 Hogg Apr. 26, 1955 2,715,621 .Hogg Aug. 16, 1955 2,736,734 Sarett Feb. 28, 1956 OTHER REFERENCES Helvetica, Chimica Acta, No. III, vol. 38 (1955), pp. 835-840. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) 11B,21-DIHYDROXY-1,4,17(20)-PREGNATRIENE-3-ONE REPRESENTED BY THE FOLLOWING FORMULA: 